Although the beneficial effects of natural and semisynthetic corticosteroids in the treatment of inflammatory and allergic conditions have been appreciated for over 35 years, clinical use of glucocorticoids as anti-inflammatory agents is limited due to their adverse systemic effects. Potent synthetic glucocorticoids with minimum salt-retaining activity have been produced by structural modifications such as introduction of a double bond, a methyl group or halogen atom on the steroid nucleus. However, little success has been achieved in separating the anti-inflammatory effects of steroids from the adverse systemic effects. These shortcomings are largely inherent in the nature of steroids themselves; not only do they possess multiple biological activities, but the structural requirements for the various activities seem to be overlapping and inseparable.
Structural modifications of the corticosteroids have been suggested to improve properties of these compounds by reducing their adverse systemic effects while retaining their anti-inflammatory properties. Another approach to minimize adverse systemic effects of steroids has involved the use of various dosage forms for local administration. Local corticosteroid preparations have been applied topically for treatment of skin disorders, injected intra-articularly for certain joint diseases, and applied as drops for ophthalmic disorders and sprayed for asthmatic conditions.
Although systemic effects are known to be reduced when conventional steroids are applied topically, the use of steroids in large quantities for prolonged periods results in toxic systemic side effects. All clinically effective topical corticosteroids have the potential for suppressing pituitary-adrenal function and the immune system, especially when large amounts are topically applied under occlusion or on an extensive area. Topical steroids are readily absorbed if the skin is damaged by disease or injury. Children are particularly prone to the systemic effects of local steroid application and suppression of pituitary-adrenal function including growth impairment has been reported. In addition, complications associated with local steroid treatment for psoriatic, rheumatologic, exzematous, asthmatic and ophthalmic disorders have been observed.
One structural modification was suggested in U.S. Pat. No. 3,944,577 to Laurent et al. wherein structural modifications of the ketol side chain on the pregnane molecule were suggested, principally the combination of a 20-carbonyl group and a 21-carboxylic acid or ester group. This provided some alleviation of the adverse systemic effects, but the compounds did not provide sufficient improvement to be widely accepted as substitutes for cortisol or prednisolone.
In my copending patent application Ser. No. 502,449 filed June 9, 1983, there are described certain prednisolone-21-carboxylic acid derivatives which were equivalent to prednisolone in anti-inflammatory activity and exhibited remarkable improvements with respect to the adverse side effects, e.g., reduced suppression of adrenal and thymus weights, better production of liver glycogen, better skin collagen synthesis, and reduced suppression of granuloma formation. Nevertheless, still greater improvement was required to provide greater acceptance for these new compounds.
It is an object of this invention to provide novel pregnane derivatives having a carboxy ester or amide group at one or more of the strategic 6.alpha.-, 6.beta.-, 16.alpha.-, 16.beta.-, or 20-positions as safer anti-inflammatory steroids. It is another object of this invention to provide novel processes for the synthesis of such steroids. Other objects will appear from the more detailed description which follows.